Event

PhD Dissertation - Camilla Edwards

Tuesday, December 17, 2024
2:00 p.m.
Richard and Rebecca Kay Boardroom, Kim Engineering Building
Rachel Chang
301 405 8268
rachel53@umd.edu

Title: Rational control of toll-like receptor signaling using microneedles for enhanced vaccination

Committee members:

Professor Dr. Christopher M. Jewell, Chair

Professor Dr. Gregg Duncan

Professor Dr. Robert Ernst, Dean’s representative

Professor Dr. Erika Moore

Professor Dr. David Mosser

Abstract:

Vaccines have been crucial technologies to prevent and stop the spread of global diseases, such as smallpox and COVID. Despite these accomplishments, more robust vaccines are needed to combat existing and emerging pathogens. Specialized subsets of cells implicated in potentiating vaccine responses known as APCs are concentrated in skin and dermal layers; thus, targeting vaccines to these cells has potential to increase vaccine potency. APCs contain toll-like receptors (TLRs) in and on their surface, which recognize toll-like receptor agonists (TLRas) - molecular patterns commonly found on pathogens but not mammalian cells. Because activating TLRs induces inflammatory responses from these cells, TLRas are clinically used as adjuvants to enhance vaccine responses against a variety of pathogens. Recent studies show that activating multiple TLRs can improve disease outcomes compared to single TLRa delivery. One way to deliver multiple TLRas is by using biomaterials, which can achieve controlled and targeted engagement of multiple TLRs on immune cells. An emerging strategy to target the APC- rich dermal layers and incorporate TLRa- containing biomaterials are microneedle arrays (MNAs), which are small patches containing hundreds of short projections to directly access the dermal immune niche.

The work in this dissertation describes novel strategies to coat and load combinations of TLRas onto and into MNAs. Specifically, two novel types of MNAs are developed and tested in vitro and in vivo. APCs and effector cells treated with coated MNAs exhibit tunable behavior as a function of the ratio of TLRa delivered. MNAs loaded with multiple TLRas and antigen are used in vivo to probe how geography and TLRa combinations affect immune responses. These MNAs enable localized, sustained cargo release over time. This localized effect extends to effector cell function, and the location of MNA application relative to disease burden directly affects disease outcomes. In addition to where MNAs are placed, the ratio of TLRa incorporated into the MNA changes gene expression, effector cell expansion, and disease outcomes. Each type of TLRa shows a gene signature indicative of a lymph node microenvironment conducive to a distinct effector cell polarization relevant to vaccination. Interestingly, this polarization is directly correlated with antigen- specific cell expansion and disease outcomes. Findings from these discoveries could hold relevance for geographically restricted diseases, such as melanomas. These results could also inform improved tunable vaccines for a variety of diseases.